Diphenyl-imidazolyl-acetic acid morpholide

ABSTRACT

1. DIPHENYL-IMIDAZOLYL-ACETIC ACID MORPHOLIDE OR THE HYDROCHLORIDE SALT THEREOF.

United States Patent US. 'Cl. 260-247.5 R 2 Claims ABSTRACT OF THE DISCLOSURE Phenyl-imidazolyl-fatty acid derivatives of the formula:

wherein R R and R are the same or different, and are hydrogen or lower alkyl;

R is hydrogen, alkyl, lower alkoxy, alkylmercapto, or an electro negative moiety;

R is benzene, benzene substituted by alkyl, lower alkoxy, alkylmercapto or an electro negative moiety, or R is an aliphatic moiety;

X is a carboxyl moiety or a grouping of a functional carboxylic acid derivative;

m is 0,1, 2, 3, 4, 5 or 6; and

n is 0, 1 or 2,

and pharmaceutically acceptable non-toxic salts thereof are produced by reacting a halogen derivative of the formula:

Hal R cm)mx wherein R R X, m and n are as above defined, and Hal is halogen,

with an optionally alkyl-substituted imidazole.

These phenyl-imidazolyl-fatty acid derivatives exhibit antimycotic activity.

This is a division of application Ser. No. 38,531, filed May 18, 1970, now US. Patent No. 3,732,242, issued May 8, 1973.

3,842,078 Patented Oct. 15, 1974 The present invention is concerned with phenylimidazolyl-fatty acid derivatives, salts thereof, and processes for their production. More particularly, the compounds of the present invention are phenyl-imidazolylfatty acid derivatives of the formula:

i i R1C\ C-R2 I (R :(om m-x wherein R R and R are the same or dilferent, and are hydrogen or lower alkyl;

R is hydrogen, alkyl, lower alkoxy, lower alkyhnercapto,

or an electro negative moiety;

R is benzene, benzene substituted by alkyl, lower alkoxy, lower alkylmercapto or an electro'negative moiety, or R is an aliphatic moiety;

X is a carboXyl moiety or a grouping of a functional carboxylic acid derivative;

m is 0,1, 2, 3, 4, 5, or 6; and

n is 0, l or 2,

and pharmaceutically acceptable non-toxic salts thereof.

These compounds are particularly useful for their antimycotic activity.

When any of the moieties R R or R are alkyl, it is preferred that they contain 1 to 4 carbon atoms.

When R is an alkyl moiety, it is preferred that it contain 1 to 4 carbon atoms, and methyl is particularly preferred. It is also preferred that the lower alkyl moieties and the lower alkylmercapto moieties contain 1 to 4 carbon atoms in the alkyl portion of the moieties. The term alkyl and lower alkyl as used herein is intended to embrace the straight as well as the branched chain alkyl moieties and includes, in addition to the alkyl moieties, the alkenyl and the alkynyl moieties as well.

Preferred electro negative substituents for R are halogen, fluorine, chlorine, bromine or iodine, chlorine being particularly preferred, N0 trifluoromethyl and cyano, as well as SO-alkyl and SO -alkyl in which the alkyl moieties contain from 1 to 6 carbon atoms and preferably from 1 to 4 carbon atoms. As above indicated, these alkyl moieties may be straight or branched-chain and include, in addition to the alkyl groups, the alkenyl and alkynyl groups as well.

When R is an aliphatic moiety, this can be straight or branched chain, saturated or unsaturated alkyl of l to 8 carbon atoms and preferably of 1 to 4 carbon atoms. The aliphatic moiety may also be a saturated or unsaturated cycloaliphatic moiety of 3 to 6 carbon atoms and preferably of 5 to 6 carbon atoms in the ring system.

Examples of functional carboxylic acid derivatives for X include esters, carboxamide and nitrile groups.

If X is an ester moiety, its alcohol portion is a substituted, straight or branched chain, saturated or unsaturated aliphatic, cycloaliphatic or heteroaliphatic moiety. If this alcohol portion contains an alkyl group, this alkyl group is straight or branched chain of 1 to 18 carbon atoms and preferably of l to 12 carbon atoms, or such alkyl group substituted by an aromatic moiety.

If X is a carboxamide moiety, it is a free carboxamide moiety, a monoalkyl-carboxamide moiety or a dialkylcarboxamide moiety wherein the alkyl portions are lower alkyl moieties, or lower alkyl moieties which may be linked to form a 5-, 6- or 7-membered ring system, or a 6-membered ring system having an oxygen, sulphur or nitrogen atom, or'a 6-membered ring having an oxygen, su1-' phur or nitrogen atom which has attached thereto a lower alkyl moiety of 1 to 4 carbon atoms which is preferably in the p-position.

The salts of the present invention are physiologically compatible salts since the compounds of the present in' (R Hal J(CH2)mX 1'1 (II) wherein R R X, m, and n are as above defined, and

Hal is halogen, preferably chlorine,

with an imidazole or an alkyl-substituted imidazole in the presence of an acid-binding base or an excess of imidazole, expediently in an inert polar solvent, such as acetonitrile, toluene, xylene, chlorobenzene, cyclohexane, acetone, diethyl ketone, dimethyl formamide or dimethyl sulphoxide, at a temperature of from about 20 C. to about 180 C., and especially of from about 50 C. to about 100 C.;

(b) Reacting 'a halogen derivative of the formula:

(B4) IIIaI z)mX E5 (II) wherein R R X, m and n are as above defined, and Hal is halogen, preferably chlorine,

with an alkali metal or silver salt of imidazole or of an alkyl-substituted imidazole in an inert solvent, such as benzene, toluene, xylene or cyclohexane at a temperature of from about 20 C. to about 200 C., and preferably from about 50 C. to 120- C.; or

(c) Reacting a hydroxy compound of the formula:

wherein R R X, m and n are as above defined with imidazole or an alkyl-substituted imidazole, with the elimination of water.

These reactions can be carried out according to procedures which are per se known, for example they may be carried out inthe melt or with the aid of the azeotropic elimination of water in the presence of higher-boiling s01- vents, such as xylene, chlorobenzene, etc., at the boiling point of the solvent used. In addition, it may be expedient at times to facilitate the elimination of water by the addition of a suitable dehydrating agent, such as alkaline earth metal oxide, for example MgO, BaO, CaO, or A1 0 The pharmaceutically acceptable non-toxic salts of the phenyl-irnidazolyl-fatty acid derivatives are, of course, obtained by reacting the free base with the corresponding acid.

According to the present invention, a preferred group of compounds is represented by the formula:

wherein R and R are both hydrogen;

R is hydrogen or methyl;

R is hydrogen, methyl, methoxy, nitro, fluorine, chlorine,

or bromine;

R is phenyl, phenyhsubstituted in the p-position by fluorine, chlorine, bromine, methyl, methoxy or nitro, or R is a straight or branched chain alkyl moiety of l to 5 carbon atoms;

X is a carboxyl group, a moiety of'the formula:

wherein R is straight or branched chain alkyl of l to 10 carbon atoms or benzyl, a moiety of the formula:

0 R ll CN wherein R and R are the same or different, and are hydrogen or methyl, or R' and R together with the amide nitrogen form a morpholino or piperidino ring, or X is a cyano moiety;

m is 0,1, 2, 3, 4, 5 or 6; and

n is 1.

Table I below lists representative phenyl-imidazolylfatty acid derivatives of the present invention.

TABLE I diphenyl-imidazolyl-acetic acid methyl ester diphenyl-i-midazolyl-acetic acid diphenyl-imidazolyl-acetic acid ethyl ester diphenyl-imidazolyl-acetic acid n-propyl ester diphenyl-imidazolyl-acetic acidisobutyl ester diphenyl-imidazolyl-acetic acid n-octyl ester diphenyl-imidazolyl-acetic acid n-decyl ester (8) diphenyl-irnidazolyl-acetic acid benzyl ester (9) diphenyl-imidazolyl-acetic acid nitrile (10) phenyl-4-methylphenyl-imidazolyl-acetic acid methyl ester (11) phenyl-Z-methylphenyl-imidazolyl-acetic acid methyl ester (12) ,B-imidazolyl-B,B-diphenyl propionic acid ethyl ester (13) hydrochloride of diphenyl imidazolyl-acetic acid methyl ester (14) phenyl-4-chlorophenyl-imidazolyl-acetic acid ethyl ester (15) phenyl-4-chlorophenyl-imidazolyl-acetic acid methyl ester 16) phenyl-2-chlorophenyl-imidazolyl-acetic acid methyl ester (17) phenyl-isopropyl-imidazolybacetic acid ethyl ester (18) diphenyl-imidazolyl-acetic acid amide l9) diphenyl-imidazolyl-acetic acid methylamide (20) diphenyl-imidazolyl-acetic acid dimethylamide (21) diphenyl-imidazolyl-acetic acid morpholide (22) diphenyl-imidazolyl-acetic acid piperidide (2'3) bis(4-chlorophenyl)-imidazolyl-acetic acid methyl ester (24) bis-(4-tolyl)-imidazolyl-acetic acid methyl ester (25) bis-(4-bromophenyl)-imidazolyl-acetic acid methyl ester (26) bis- (4-fiuorophenyl)-irnidazolyl-acetic acid methyl ester and the hydrochloride salt thereof (27) bis-(4-methoxy-phenyl)-imidazolyl-acetic acid methyl ester (28) bis-(4-nitro-phenyl)imidazolyl-acetic acid ethyl ester hydrochloride (29) phenyl-isopropyl-imidazolyl-propionic acid ethyl ester 1 (30) phenyl-isopentyl-imidazolyl-propionic acid ethyl ester (31) phenyl-ethyl-imidazolyl-isobutyric acid methyl ester (32) diphenyI-Z-methyl-imidazolyl-acetic acid methyl ester (-33) phenyl-tert.-butyl-imidazolyl-acetic acid methyl ester (34) 'diphenyl-irnidazolyl-acetic acid methyl ester-tartrate 35) diphenyl-imidazolyl-acetic acidmethyl estersuccinate (36) diphenyl-imidazolyl-acetic acid methyl ester sulphate (37) diphenyl-imidazolyl-acetic acid methyl estermethane-sulphonate (38) diphenyl-imidazolyl-acetic acid methyl esternaphthalene-1,5-disulphonate.

Particularly preferred compounds according to the present invention are diphenyl-imidazolyl-acetic acid methyl ester and the hydrochloride salt thereof.

The starting materials required for the preparation of the, compounds of the present invention are per se known or are obtainable according to processes which themselves are known per se. v

The following non-limitative examples more particularly point out and illustrate the present invention.

EXAMPLE 1 I 113 g. (0.05 mole) diphenyl-chloroacetic acid methyl ester (b.p. 140 C./ 0.1 mm. Hg, prepared from diphenylchloroacetic acid chloride and methanol according to Ber. 22, 1537) are heated with g. imidazole in- 100 ml. acetonitrile at boiling temperature for 18 hours. After dis tilling off the solvent in a vacuum, 50 ml. of Water are added and the mixture is extracted with methylene chloride. After drying over sodium sulphate, the solvent is distilled off in a vacuum and the residue recrystallized from a little ethyl acetate. The diphenyl-imidazolyl-acetic acid methyl ester is thus obtained in the form of colourless crystals of m.p. 155 C. (with decomposition).

, EXAMPLE 2 The corresponding carboxylic acid i.e. diphenyl-imidazolyl acetic acid is obtained by hydrolysis of the diphenyl-imidazolyl-acetic acid methyl ester obtained in -Ex-- ample l, with an alcoholic potassium hydroxide solution.

EXAMPLES 3-8 The compounds of these Examples were obtained according to the procedure set forth in Example 1, by reacting imidazole with the following reactants:

' From 13.7 g. diphenyl-chloroacetic acid ethyl ester (0.05 mole) (Ber. 22, 1537): the diphenyl-imidazolylacetic acid ethyl ester of m.p. 104 C.

From 14.4 g. diphenyl-chloroacetic acid propyl ester (b.p. 155 C./0.3 mm. Hg): the diphenyl-imidazolylacetic acid n-propyl ester of m.p. 71 C.

' From 15.1 g. diphenyl-chloroacetic acid isobutyl ester (b.p. 150 C./0.2 mm. Hg): the diphenyl-imidazolylacetic acid isobutyl ester as oil.

From 16.0 g. diphe'nyl-chloroacetic acid octyl ester (b.p. 195 C./ 0.3 mm. Hg): the diphenyl-imidazolyl-acetic acid n-octyl ester as oil.

From 19.3 g.- diphenyl-chloroacetic acid decyl ester: the diphenyl-imidazolyl-acetic acid n-decyl ester of m.p. 48 C.

From 16.8 g. diphenyl-chloroacetic acid benzyl ester: the diphenyl-imidazolyl-acetic acid benzyl ester as oil.

6 EXAMPLE 9 5.9 g. diphenyl-chloroacetonitrile (prepared from diphenylchloroacetamide, Ber. 41, 3593 by heating in phosphorus oxychloride; b.p. C./ 0.4 mm. Hg) are heated with 5 g. imidazole in 50 ml. acetonitrile at boiling temperature for 18 hours. After treating with 20 ml. of water, the mixture is extracted with methylene chloride. The solvent is distilled off after drying in a vacuum. The solid residue is recrystallized from ethyl acetate/petroleum ether. Diphenyl-imidazolyl-acetonitrile i.e. diphenylimidazolyl-acetic acid nitrile of m.p. 98 C. is thus obtained.

EXAMPLE 10 13.7 g. phenyl-p-tolyl-chloroacetic acid methyl ester (prepared from p-tolyl-magnesium bromide and benzoylformic acid methyl ester and treatment with PCl b.p. C./0.3 mm. Hg) are heated with 10 g. imidazole in 100 ml. acetonitrile at boiling temperature for 16 hours. The acetonitrile is distilled off in a vacuum. The residue is treated with 50 ml. of water and then extracted With methylene chloride. The methylene chloride solution is distilled 00? in a vacuum and the residue recrystallized from a little ethyl acetate. The phenyl-p-tolyl-imidazolylacetic acid methyl ester i.e. phenyl-4-methylphenyl-imidazolyl-acetic acid methyl ester of m.p. 146 C. is thus obtained.

EXAMPLE 11 The phenyl-o-tolyl-imidazolyl-acetic acid methyl ester i.e. phenyl-2-methylphenyl-imidazolyl-acetic acid methyl ester (m.p. 148 C.) is obtained in an analogous way from phenyl-o-tolyl-chloroacetic acid methyl ester (b.p. C./0.4 mm. Hg).

EXAMPLE 12 14.4 g. (0.05 mole) [3 chloro- 8,,8-diphenyl-propionic acid'ethyl ester (prepared from fl-hydroxy-[LB-diphenylpropionic acid ethyl ester, Ber. 40, 4538, by treatment with phosphorus pentachloride) are heated in 100 ml. acetonitrile with 10 g. imidazole at boiling temperature for 16 hours. The solvent is distilled off in a vacuum, the residue treated with 50 ml. of water and extracted with methylene chloride. After drying, the solvent is distilled off in a vacuum. The B-imidazolyl-5,;3-diphenyl-propionic acid ethyl ester is thus obtained in the form of crystals of m.p. 75 C.

EXAMPLE 13 5 g. of the diphenyl-imidazolyl-acetic acid methyl ester of Example 1. are dissolved in carbon tetrachloride and hydrogen chloride is introduced with cooling. The carbon tetrachloride is decanted off from the precipitated oily salt and the salt is reprecipitated from acetone/ ether. The hydrochloride of-the above base i.e. diphenyl-imidazolylacetic acid methyl ester hydrochloride is thus obtained; m.p. 131 C. (decomp.).

EXAMPLE 14 15.45 g. (0.05 mole) and phenyl-p-chlorophenyl-chloroacetic acid ethyl ester (prepared from p-chlorophenylmagnesium bromide and benzoyl-formic acid ethyl ester and subsequent treatment with thionyl chloride: b.p. 160 C./0.2 mm. Hg) are boiled with 10 g. imidazole in 100 ml. acetonitrile for 16 hours. After distilling off the solvent, 50 ml. of Water are added, and the mixture 7 is extracted with methylene chloride. After drying, the solvent is distilled 01f in a vacuum and the phenyl-pchlorophenyl-imidazolyl-acetate acid ethyl ester i.e. phenyl-4-chlorophenyl-imidazolyl-acetic acid ethyl ester is obtained in the form of an oil which solidifies after a fairly long time.

EXAMPLE The phenyl-p-chlorophenyl-imidazolyl-acetic acid methyl ester i.e. phenyl-4-chlorophenyl-imidazolyl-acetic acid methyl ester of melting point 135 C. (ethyl acetate) is obtained in an analogous way by reacting phenyl-p-chlorophenyl-chloroacetic acid methyl ester and imidazole.

EXAMPLE 16 The phenyl-o-chlorophenyl-imidazolyl-acetic acid methyl ester i.e. phenyl-2-chlorophenyl-imidazolyl-acetic acid methyl ester of melting point 138 C. (ethyl acetate) is obtained by the method described in Example 14 by reacting phenyl-o-chlorophenyl-chloroacetic acid methyl ester and imidazole.

EXAMPLE 17 12 g. (0.05 mole) phenyl-isopropyl-chloroacetic acid ethyl ester (b.p. 95 C./0.3 mm. Hg) are heated with 10 g. imidazole and 100 ml. acetonitrile at boiling temperature for 18 hours. After distilling off the solvent in a vacuum, 50 ml. of water are added and the mixture is extracted by shaking with methylene chloride. The methylene chloride is dried and distilled off in a vacuum. The phenyl-isopropyl-imidazolyl-acetic acid ethyl ester is thus obtained in the form of an oil.

EXAMPLE 18 12.27 g. (0.05 mole) diphenyl-chloroacetic acid amide (Ber. 41, 3593) are heated with 11.8 g. imidazole in 100 ml. acetonitrile at boiling temperature for 18 hours. After cooling, the crystals are suspended in water and rinsed. After recrystallization from methanol, diphenyl-imidazolyl-acetic acid amide of m.p. 218 C. is obtained.

EXAMPLE 19 13 g. (0.05 mole) diphenyl chloroacetic acid methylamide (prepared from diphenyl-chloroacetic acid chloride and methylamine in analogy with Ber. 41, 3593; m.p. 108 C.) are heated with 11.5 g. imidazole in 100 ml. acetonitrile at boiling temperature for 18 hours. After cooling, the crystals are filtered off with suction, digested with water and rinsed. After recrystallization from methanol, diphenyl-imidazolyl-acetic acid methylamide of b.p. 237 C. is obtained.

EXAMPLE 20 EXAMPLE 21 The diphenyl-imidazolyl-acetic acid morpholide is obtained from 15.5 g. diphenyl-chloroacetic acid morpholide (m.p. 113 C.) and 11 g. imidazole in 100 ml. acetonitrile on analogy with Example 20.

The hydrochloride of diphenyl-imidazolyl-acetic acid morpholide. of m.p. 118 C. is obtained by adding ethereal hydrochloric acid to a solution of diphenyl-imidazolylacetic acid morpholide in ethyl acetate.

8 EXAMPLE 22 The diphenyl-imidazolyl-acetic acid piperidide of m.p. 160 C. is obtained from 15.4 g. diphenyl-chloro-acetic acid piperidide (m.p. 82 C.) and 10 g. imidazole in 100 ml. acetonitrile in analogy with Example 20.

EXAMPLE 23 162.6 g. (0.434 mole) of 4,4-dichlorodiphenylbromoacetic acid methyl ester (prepared from 4,4'-dichlorobenzilic acid methyl ester) and phosphorus pentabromide (b.p. 190/0.5 mm. Hg) are heated to the boil for 14 hours, with stirring, with g. (1.32 mole) of imidazole in 1 litre of acetonitrile. The acetonitrile is distilled off in a vacuum. For the removal of imidazole, the residue is twice shaken with, in each case 1.3 litres of water, then taken up in 950 ml. of methylene chloride and again extracted with 1.8 litres of water. After drying with sodium sulphate, the methylene chloride is distilled in a vacuum. The residue is boiled out four times with, in each case, 250 ml. of ether; the ethereal solution, after clarification with charcoal, is precipitated with ethereal hydrochloric acid. The precipitate is digested with absolute ether and taken up in methylene chloride; after filtration, ethyl acetate is added. When the methylene chloride is evaporated on a waterbath, the hydrochloride of bis-(4-chlorophenyl)-imidazolyl-acetic acid methyl ester of the melting point 150 C. (with decomposition) crystallizes out in colourless crystals.

When the hydrochloride is shaken with methylene chloride and solution of sodium carbonate, a solution of the base is obtained. After this has been dried, distillation in a vacuum is effected and the residue is recrystallized from dry ether. There are so obtained the colourless crystals of bis(4-cl1lorophenyl)-imidazolyl-acetic acid methyl ester of the melting point 132 C.

EXAMPLE 24 Analogously with Example 23, there is obtained from 13.3 g. 4,4-ditolyl-a-bromoacetic acid methyl ester and 10 g. imidazole in ml. acetonitrile the hydrochloride of bis-(4-tolyl)-imidazolyl-acetic acid methyl ester of the melting point 140 C. (with decomposition) in colourless crystals.

EXAMPLE 25 19.4 g. 4,4'-dibromodiphenylbromoacetic acid methyl ester (prepared from 4,4'-dibromodiphenylacetic acid methyl ester and bromosuccinimide) are heated to the boil for 15 hours with 8.4 g. imidazole in 8.5 ml. acetonitrile. The acetonitrile is distilled off in a vacuum. The residue is shaken twice with, in each instance, m1. of water and decanted. The residue is taken up in about 100 ml. of methylene chloride and again extracted with 80 ml. of water. After drying of the methylene chloride, the latter is distilled off in a vacuum. The residue is boiled out four times with, in each case, 100 ml. of absolute ether. The ether is clairified with charcoal and precipitationis effected with ethereal hydrochloric acid. The hydrochloride precipitating in lumps is digested twice with absolute ether, then taken up in methylene chloride. After filtration, ethyl acetate is added, and the methylene chloride is evaporated on a water-bath. After cooling, the hydrochloride of bis- (4-bromophenyl)-imidazolyl-acetic acid methyl ester of the melting point 140 C. crystallizes out in colourless crystals.

The hydrochloride is shaken with methylene chloride and solution of sodium carbonate. The solution of the base in methylene chloride is dried and distilled off in a vacuum. The residue is recrystallized from a little absolute ether. There are so obtained the colourless crystals of bis-(4-bromophenyl)-imidazolyl-acetic acid methyl es ter acid methyl ester of the melting point C.

9 EXAMPLE 36 In the same manner as in Example 23, there is obtained from 40.1 g. 4,4'-difluorodiphenylbromoacetic acid methyl ester (b.p. 143/ 0.4 mm. Hg, prepared from 4,4-difluo rodiphenylacetic acid methyl ester and N-bromosuccinim'id'e) and 236g. imidazole in 236 ml. acetonitrile the hydrochloride of bis-(4 fluorophenyl)-imidazolyl-acetic acid methyl ester of the melting point 147 C. From this there is obtained, with solution of sodium carbonate in methylene chloride, the free base of the melting point 12 c- EXAMPLE 27 In the same. manner as in Example 23, there is obtained from 4,4'-dimethoxybenzilicacid methyl ester (m.p. 110 C.) with phosphorus pentachloride via 4,4'-dimethoxyphenyl-a-chloroacetic acid methyl ester with imidazole in acetonitrile the bis-(4 methoxyphenyl)-imidazolyl-acetic acidmethyl ester of the melting point 131 C.

EXAMPLE 28 In the same manner as in Example 23, with analogous working up, there is obtained from 10.25 g. 4,4'-dinitrodiphenylbromoacetic acid ethyl ester (m.p. 130 C., prepared from 4,4'-dinitrodiphenylacetic acid ethyl ester and N-bromosuccinimide) and g. imidazole in 70 ml. acetonitrile the hydrochloride of his (4 nitrophenyl)-imidazolyl-acetic acid ethyl ester of the melting point 130 C. (with decomposition) in colourless crystals.

EXAMPLE 29 Analogously with Example 12, by reacting chlorophenylisopropyl-propionic acid ethyl ester and imidazole, phenyl-isopropyl-imidazolyl-propionic acid ethyl ester is obtained as oil, and from this there is obtained, with ethereal hydrochloric acid, the hydrochloride of the melting point 194 C.

' EXAMPLE 30 Analogously with Example 12, by reacting chlorophenylisopentyl-propionic acid ethyl ester and imidazole, phenyl-isopentyl-imidazolyl-propionic acid ethyl ester is obtained as oil.

EXAMPLE 31 Z-methyl-imidazole in ml. acetonitrile. The acetonitrile is distilled off in a vacuum. 200 ml. of water are added to the residue, which is then taken up in 200 ml. methylene chloride. The methylene chloride is extracted twice with, in each case, 150 ml. of water, dried and distilled off in a vacuum. The residue is recrystallized from a little ethyl acetate. There is so obtained the diphenyl-2-methyl-imidazolyl-acetic acid methyl ester of the melting point 136 C.

EXAMPLE 33 12.7 g. (0.05 mole) phenyl-tert.-butyl-chloroacetic acid methyl ester (b.p. 96 C./0.3 mm. Hg) are heated to the boil for 17 hours with 10 g. imidazole and 100 ml. acetonitrile. After the solvent has been distilled oil in a vacuum, treatment with 70 ml. of water is effected followed by extraction with methylene chloride. The methylene chloride is again extracted with 30 ml. of water, dried and distilled off in a vacuum. There is so obtained the phenyl-tert.-imidazolyl-acetic acid methyl ester as oil, which solidifies after a long time.

EXAMPLE 34 From the diphenyl-imidazolyl-acetic acid methyl ester obtainable according to Example 1 and the appropriate acid listed, the following salts of diphenyl-imidazolylacetic acid methyl ester are obtained:

Acid Salt Melting point Tartaric Tartrate C. (tlee0mp.). Succinie Succinate 107 C. (deeomp.). Sulphuric Sulphate C. (decomp.). Methane-sulphonic Methane-sulphonate 154 C. (decomp.).

Naphthalene-1,5- disulphonic.

N aphthalene-1,5-

229 C. (deeomp.) disulphonate.

(a) in the case of dermatophytes and mould fungi, in

Sabourauds milieu depreuve, (b) in the case of yeasts, in yeast/meat broth bouillon.

The incubation temperature was 28 C. and the duration of incubation was 48 to 96 hours.

TABLE II Minimum inhibition concentration in 'y/ml. test medium in the case of- Trichophyton ment. Candida albicans Aspergillus niger Compound om Without With Without With Pen. Without With Microsp. Exampleserum serum serum senlm comune serum serum felineum TABLE III Minimum inhibition concentration in 'y/ml. nutrient medium Trichophyton mentagrophytes Candida albicans Aspergz'llus m'ger Hystel Penicil- Microplas'ma Coccz'd- With Without With Without Zium With Without sporon capsuiodes 1Compound from Exampleserum serum serum serum commie serum serum felineum Zatum immitis 23 ase 23 (hydrochloride) (base) 25 (hydrochloride) The following compounds representative of those of the In the case of a parenteral administration of the compresent invention were tested for in-vivo activity according pound from Example 13 in a dosage of 25 mg./kg. twice to the procedures set forth below: daily, 18 to 20 animals survived 6 days after the infection. 5 (C) Local treatment of experimental guinea-pig trichodqifiznly; lmidazolyl acetic acid methyl ester (Exam phytosislwith the compound from Example 13- diphenyl imidazolYLacetic acid ethyl ester (EXamp1e 3) Infection of the animals was effected by Irichophyton diphenyl-imidazolyl-acetic acid n-propyl ester(EXami q y From the 3rd after p the P 4) bngectilonfpoiiitty was trezgtedlotnce dully by application 0; m o a 0-5 rengt so 11 mm o t e active compoun 132 lmldazolyl acetlc acld 1S0 butyl ester (Exam in polyethyleneglycol 400. This treatment was continued up to the 14th day after infection. Within the therapy g g fig g f nmdazolyl acetlc acid methyl period, the dermatosis healed up. In the case of untreated infected control animals, bleeding ulcerations of the diphenyl-imidazolyl-acetic acid methyl ester hydrochloride (Example 13) infection point as well as loss of hair occurred up to about 30 days after infection.

111" 1- 2 53 533331? 213 acid morp Olde hydrocho The phenyl-nnidazolyl-fatty acid denvatwes and the bis-(4-chlorophenyl)-imidazolyl-acetic acid methyl esterpharmac'iutlcany accepiable gm-tome are thus particularly useful in treating the following diseases: (Examp 1e 23) (a) In human medicine bis-(4-chlorophenyl)-imidazolyl-acetic acid methyl ester (l) Dermatomycoses caused by fung1 of the species hydrochlonde(EXampl6 23) Tricho h tes Micros oriu E ide h t A l bis-(4-bromopheny1)-imidazolylacetic acid methyl ester lus i g f gg y Spergl (base)(Example 25) bis-(4-bromophenyl)-imidazolyl-acetic acid methyl ester q grghantomycoses caused by yeasts mould fungl and hydrochloride (EXamp 1e 25) b) In vZt::inar medicine' Dermatom co e nd rbis-(4-fiuorophenyl)-imidazolyl-acetic acid methyl ester y y S S a 0 hydrochloride (Example 26) ganomycoses by yeasts, mould fungi and Dermatophytes. bis-(4-methoxyphenyl)-imidazolyl-acetic acid methyl ester T compounds of the present .lvennon may be admin" (base)(EXample 27) lstered orally, parenterally or topically. bis-(4-nitrophenyl)-imidazolyl-acetic acid ethyl ester hyg ig g 52111 2; :;gg g sgggz gg figasg gg; drochlonde(Example 28) day in order to achieve satisfactory results, it is to be (A) Oral treatment of experimental candidiasis of the appreciated that it may be necessary to deviate from these white mouse with the compounds of Examples 1, 3, 4, ranges and that a variety of factors such as the body 5, 11, 13, 21, 23, 25, 26, 27 and 28. weight of the test animal or patient, the method of ad 66 mice of the strain CF S'PF of 2022 g. weight ministration, the animal species, the past medical history were infected intravenously with 25 10 Candida albiof the patient, the individual reaction to the medication, cans cells per mouse. With this exprirnental arrangement, the type of formulation, and the moment in time or the untreated animals died of the infection within 6 days. time interval at which it is to be administered are all When 3060 mg. of these compounds per kilogram among the factors which are to be taken into considerabody weight of the infected animals was administered tion. It may in certian cases be sufficient to use less than orally once or twice daily, an average of 13 to 16 of the the above indicated minimum amount, whereas in other 20 animals receiving the administration survived on the cases it may be necessary to administer more than the 6th day after infection. In the case of treatment with the above indicated amount. If larger amounts are to be compound of Example 13, 19 to 20 of the animals of administered, it is preferred that these be administered the group of 20 survived. The optimum dosage for the in several dosages during the course of the day. compounds of Examples 1, 3, 5, 13, 23 and 28 was shown Also according to the present invention are pharmato be 50 mg./kg. twice daily. The optimum dosage for ceutical compositions which comprise the phenyl-imidcompounds of Examples 4, 11, 21, 25, 26 and 27 was azolyl-fatty acid derivatives or the pharmaceutically shown to he 60 mg./=kg. twice daily. acceptacle non-toxic salts thereof in combination with For oral application, the preparation were suspended pharmaceutically acceptable non-toxic carriers and diluin 0.25 %-strength glucose-agar and administered with the ents. Suitable forms of application, in combination with oesophageal sound. various inert carriers, are the following: tablets, capsules,

(B) Parenteral treatment of experimental candidiasis powders, sprays, aqueous suspensions, injectable soluand histoplasmosis of the mouse with the compound tions, elixirs, syrups and the like. Such carriers comprise from Example 13. solid diluents or fillers, a sterile aqueous medium as well as non-toxic organic solvents and the like. Tablets and the like intended for oral application may, of course, be provided with sweetening additives and similar substances. In the aforesaid case the therapeutically active compound should be present at a concentration of about 0.5 to 90 percent by weight of the total mixture, i.e. in quantities which are sulficient to achieve the range of dosage mentioned above.

The pharmaceutical compositions according to the present invention may include a protective envelope containing the active compound and if the compound is in combination with a diluent or carrier, the envelope may contain said diluent or carrier as well.

The term medicament in dosage unit form as used in the present specification means a medicament as defined above in the form of discreate portions of each containing a unit dose, or a multiple or sub-multiple of a unit dose of the active compounds or compounds. Such portions may, for example, be in monolithic coherent form, such as tablets, suppositories, pills or dragees; in wrapped or concealed form, such as wrapped powders, cachets, sachets, or capsules; in ampoules, either free or as a sterile solution suitable for parenteral injection; or in any other form known to the art.

In the case of oral application, the tablets can obviously also contain additives, such as sodium citrate, calcium carbonate and dicalcium phosphate together with various other additives, such as starch, preferably potato starch, and the like, and binding agents, such as polyvinylpyrrolidone, gelatin and the like. Lubricants, such as magnesium stearate, sodium lauryl sulphate and talc may also be added for the production of tablets. In the case of aqueous suspensions and/ or elixirs which are intended for oral application, the active substances may be used with various flavouring agents, colouring substances, emulsifiers and/or together with diluents, such as water, ethanol, propylene glycol, glycerol and similar compounds or combinations of this type.

In the case of parenteral application, solutions of the active substances in sesame or peanut oil, or in aqueous propylene glycol or N,N-dimethyl formamide can be used as can sterile aqueous solutions in the case of water-soluble compounds. Aqueous solutions of this kind should be buffered in usual manner if necessary; furthermore, the liquid diluent should previously be rendered isotonic by the addition of the necessary amount of salt or glucose. Such aqueous solutions are particularly suitable for intravenous, intramuscular, intraperitonel and subcutaneous injections. Sterile aqueous media of this kind are prepared in known manner.

Local application is efiected in the form of 0.5-5%, preferably 1%, solutions (for example in dimethyl formamide, glycerol, water; alcohol, such as ethanol and 14 isopropanol and buffer solutions), but also as emulsions, suspensions, powders and tablets.

When the compounds of the present invention are administered, they may of course be administered either in the form of a free base or in the form of a pharmaceutically acceptable non-toxic salt thereof. Thus, the free base and the salts may be contained in capsules, tablets, pastilles, dragees and ampoules, and the like for oral administration which is a particularly facile mode of administration.

The phenyl-imidazolyl-fatty acid derivatives and the pharmaceutically acceptable non-toxic salts thereof, or the pharmaceutical compositions above described may be formulated in unit dosage form wherein each dosage unit is so formulated that it provides a single dose of the active compound, or it may contain a plurality of doses, or a fraction of a dose. Common dosages include two, three or four doses or a half, quarter or third of a dose.

While hitherto known antimycotics, are effective only against yeasts, such as amphotericin B, or only against zygomycetes, such as griseofulvin, the compounds of the present invention even upon oral administration are effective against yeast as Well as against zygomycetes. In

particular, the compounds of the present invention exhibit substantially less toxicity than amphotericin B and their effectiveness is substantially greater than that of griseofulvin.

In addition to their antimycotic activity, the compounds of the present invention also exhibit activity against pathogenic protozoa, such as trypanosomes, tri chomonades, Entamobea histolytica, causative organisms of malaria, as well as an activity against gram-positive cocci, such as staphylococci, and against gram-negative bacteria, such as E coli. When the compounds of the present invention are administered to humans or animals for such activity, they are administered in the same general manner and amounts as known compounds exhibiting those activities.

What is claimed is:

1. Diphenyl-imidazolyl-acetic acid morpholide or the hydrochloride salt thereof.

2. The compound according to claim 1, which is diphenyl-imidazole-acetic acid morpholide.

No references cited.

DONALD G. DAUS, Primary Examiner J. TOVAR, Assistant Examiner U.S. Cl. X.'R.

260247.1 B, 247.2 A, 247.2 B, 247.7 

1. DIPHENYL-IMIDAZOLYL-ACETIC ACID MORPHOLIDE OR THE HYDROCHLORIDE SALT THEREOF. 